Is It Possible to Make a Less Allergenic Peanut?

Why scientists and startups are tinkering with our most popular legume.

CreditCreditIllustration by Paul Sahre

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By Roxanne Khamsi

Dec. 15, 2016

In the summer of 1987, Wesley Burks, a pediatric allergist in Little Rock, decided to enroll in a graduate-level biochemistry course at the University of Arkansas. Twice a week, instead of driving to his laboratory at the Arkansas Children’s Hospital, he headed to the medical-school campus about a mile away. There, he joined some 20 students learning to pipette liquid extracts into gels and stain them with pigments to figure out which protein molecules they contained. Burks had only recently completed his medical fellowship, where he studied why some children have allergic reactions to milk and eggs. Now he was throwing himself into biochemistry so he could be the first to figure out what it was about peanuts that made people so allergic. “It’s easy to say you want to do something that’ll change kids’ lives,” Burks says. “But you have to focus on an area to really get it done.”

After finishing the summer course, Burks began making regular trips to a peanut farm in northeast Arkansas. “They let me drive out in the field in our station wagon and dig up a few rows of peanuts so that we’d have enough to bring back to the lab,” Burks recalls. At the lab, he placed the peanuts on pans and roasted them in ovens. A mouthwatering aroma filled the room as Burks ground the peanuts into a paste with a mortar and pestle for use in his experiments.

The fragrant mush was then dumped into three-foot-tall tubes containing a thick cellulose mixture to help isolate proteins. The isolated proteins were ultimately transferred onto pieces of paper and soaked in blood serum from peanut-allergic patients. The goal was to figure out which proteins would bind to molecules in the serum, an indication that the particular protein was responsible for creating an allergic immune response. It was a laborious process, taking months of trial and error to get any answers at all.

Finally, in 1990, he identified an offender: an allergenic protein named Ara h 1, after the Latin name for the peanut: Arachis hypogaea. Around that time, for reasons that remain unclear, the prevalence of peanut allergy among children in the United States began increasing, and more than quadrupled between 1997 and 2010, to about one in 50 from one in 250. More than three million people are now estimated to be allergic to peanuts or tree nuts or both. One possible explanation, known as the hygiene hypothesis, posits that because the immune system doesn’t encounter as many dangerous germs in our increasingly sterile modern living spaces, it starts overreacting to benign substances, like peanuts and wheat. Another idea, posited by Nicholas Christakis, a sociologist at Yale University, is that an exaggerated fear of nut allergies is encouraging more and more parents to have their children tested. Test results can be misleading. They can pick up “mild and meaningless ‘allergies’ to nuts” in children who do not actually need to avoid this food, Christakis wrote in the British medical journal BMJ.

Allergic reactions to peanuts cause around 500 hospitalizations and even some deaths in the United States each year. Food that contains trace amounts, because it was produced with factory equipment or kitchen tools that came into contact with peanuts, can prove fatal for allergic individuals who consume it unsuspectingly. Accidentally ingesting as little as a third of a single peanut — about 70 milligrams — can send someone to the emergency room, and some people may react to only 1 milligram, says Burks, who is now a leading allergy researcher.

For a long time, the only way to address peanut allergies involved creating peanut-free spaces in schools and on planes, changing individual behaviors or ensuring the availability of emergency medical treatments like the controversially high-priced EpiPen. Doctors have tried feeding patients minuscule amounts of peanuts to gradually retrain their immune systems to become tolerant of the food, but the treatment doesn’t always work. Now a growing number of researchers from separate fields are converging on an entirely different approach. Rather than changing people, they say, we should change the peanut.

Twice a month, inside a nearly windowless former school-cafeteria kitchen on the outskirts of Greensboro, N.C., scientists working at a food-technology start-up, Alrgn Bio, pour several pounds of roasted peanuts into a steaming eight-quart stainless-steel tank. The peanuts swirl in the humming tank for several hours in a warm bath of water mixed with a commercially produced enzyme called Alcalase. In the years since Burks’s first discovery, researchers have identified 16 other peanut proteins that are allergenic. Alcalase works within the peanuts to destroy the biologically reactive parts of these types of proteins to varying degrees while leaving the peanuts’ natural form intact. The hope is that the proteins are so changed that they won’t be recognized by the immune system — and will be less likely to elicit an allergic reaction, or at least a deadly one — in someone with the allergy.

The peanut-cleansing method used by Alrgn Bio evolved from experiments dating back to 2005, when biochemists at North Carolina Agricultural and Technical State University in Greensboro started mixing peanut extracts with trypsin, an enzyme found in the human intestine, to see whether the enzyme could break down the proteins that Burks and others discovered were causing allergies. The university researchers later turned to Alcalase, an enzyme that can break down an even broader range of proteins and that is used in some foods like marinades. (It’s also found in laundry detergent, where it chews up stains from protein-rich foods like eggs and gravy.) The Alcalase-treatment process now yields peanuts that look similar to those sold at the supermarket, aside from being a slightly darker shade. For the most part, the samples I tried tasted like ordinary nuts, though perhaps missing some of their earthy complexity. Alrgn Bio is still refining the process of altering its peanuts, which are currently called Safer Peanuts, to retain all their natural flavor.

Ann Russell is the operations director for Alrgn Bio. For 25 years, she ran a computer-application training business from her home, sending her two children to school each day with peanut-butter-and-jelly sandwiches. In 2014 her husband, Ken Russell, who had worked as a facilitator of technology transfers between universities and companies, licensed the special enzyme treatment from North Carolina A&T with a business partner. Within a year, Ann was helping to turn academic peanut research into a business. The start-up secured an early strategic investment from the New York real estate developer Kit McQuiston, whose daughter is allergic to peanuts. McQuiston has continued to support Alrgn Bio, helping to fund the company’s move to a larger space a year ago and taking on the role of chief executive in June. The start-up has sent samples to several major food manufacturers and is conducting further research, with the hope of putting the Safer Peanut on the market in the next few years.

A number of other teams have also tried various ways to make peanuts less lethal. A 2008 study led by a U.S.D.A. scientist showed that the shocks produced by pulsed ultraviolet light significantly reduced the allergenicity of peanut extracts in a lab test. Researchers in China have tried irradiating peanut extracts with gamma rays to make them less allergenic. In July, an Australian group trying to develop peanuts that can be used to retrain the immune system reported that boiling raw peanuts for up to 12 hours in deionized water degraded some of the harmful proteins. But those boiled peanuts are still somewhat allergenic, as well as shriveled and tasteless, according to Tim Chataway, a protein specialist at Flinders University who helped conduct the study. “The most common comment from patients who eat the peanuts is that they taste like cardboard,” he says.

Improvements in genetic-engineering tools have given molecular biologists the means to stop the peanut plant from producing some of the allergenic proteins in the first place. One of the first to try was Peggy Ozias-Akins, who leads the Institute of Plant Breeding, Genetics and Genomics at the University of Georgia. In the mid-2000s, Ozias-Akins spent hours in the lab using a scalpel to pick out the tiny nub situated atop the inner crease of each peanut seed. As this nub — the peanut embryo — grew in a petri dish, she would blast it with pressurized air to deliver microscopic DNA molecules into its cells, where they shut down the production of allergenic proteins. Ozias-Akins and her colleagues succeeded in engineering nuts with radically lower levels of Ara h 2 and Ara h 6 proteins, two especially potent peanut allergens.

Follow-up experiments conducted by Ozias-Akins in recent years have demonstrated that once allergenic genes are silenced, they stay that way through multiple generations of the peanut plant. Ozias-Akins hopes to try to use Crispr, a new tool for genetic manipulation, to enable swifter and easier DNA editing. In February, she and an international group of scientists sequenced the peanut’s genome for the first time, which could help guide future genetic engineering of the crop.

One plant biologist, Hortense Dodo, has already started a company to develop genetically modified peanuts for eventual sale. She began trying to alter the peanut while at the Alabama Agricultural and Mechanical University. She now has a company called IngateyGen, which is seeking to develop a genetically modified hypoallergenic peanut she calls Peanut4Life.

But an unresolved question is how many of the 17 known allergenic proteins scientists can actually edit out of the peanut. Ara h 1 helps the seed store energy for growth, for example, while Ara h 13 helps fight off fungi. Researchers may discover that removing every allergy-causing protein may ​​have the unintended consequence of destroying the viability of the plant itself.

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CreditIllustration by Paul Sahre

In the basement of a new glass building on the University of North Carolina’s campus in Chapel Hill, lives a colony of mice with special immune systems that have been sensitized to be allergic to peanuts. When they are given peanut slurry, they experience reactions ranging from itchy snouts to anaphylactic shock. These mice react even to trace amounts of peanut, making it possible to simulate the response to the small amounts that might be present through cross-contamination. After the rodents ingest this food through a tube and their symptoms are monitored, their blood is drawn and taken across the street to the labs of the Food Allergy Initiative. The initiative is affiliated with the university’s medical school, where Wesley Burks is now executive dean. In the next few months, in a study sponsored by Alrgn Bio, colleagues collaborating with Burks plan to begin feeding the rodents an extract from Safer Peanuts to see whether the enzyme-treatment process helps prevent an allergic response.

The results of the mouse study may not be known for a year or longer, but it builds upon research begun several years ago involving an earlier version of Alcalase-treated peanuts. In that clinical experiment, researchers applied microscopic amounts of extracts from treated and untreated peanuts on the inner forearms of nine human volunteers with peanut allergies and looked for any skin flare-ups. The results of this classic “skin prick” test were encouraging: Bathing the peanuts with Alcalase for three hours resulted in as much as a 60 percent reduction in the allergic response. Moreover, several participants had no allergic sensitivity whatsoever to the enzyme-treated peanut samples. Since then, Russell’s team has refined its Alcalase technique, further reducing the peanuts’ levels of Ara h 1, Ara h 2 and Ara h 6.

In the trial, though, the skin of a couple of the volunteers still reacted strongly to the treated peanuts. This underscores the challenge of engineering hypoallergenic foods: People may react to different peanut proteins, and some individuals are more sensitive than others. It’s hard to guarantee that Safer Peanuts would be safe for everyone to eat, even if they contained sharply reduced levels of certain allergens. For this reason, Russell says her product is not designed for peanut-allergic individuals to consume but rather for those who already eat ordinary peanut products. Her immediate goal is for a major food brand to make a special peanut butter with Safer Peanuts that, say, would be permitted at schools that ban regular peanut products to protect allergic students. But down the line Russell imagines major companies using Safer Peanuts more broadly in other products, both to eliminate deadly cross-contamination in the manufacturing process and accidental consumption in snacks and foods with hidden peanuts. “If you have a peanut-allergic child, this product would give you confidence to send your child out into the world where a peanut could creep into their lives,” Russell says, though this scenario faces substantial obstacles.

To even begin to try to realize this dream, industry experts say, the enzyme would have to work consistently within each batch. “You would have to be 100 percent sure that it penetrated every single peanut,” explains Patrick Archer, president of the American Peanut Council. He is similarly skeptical about applying genetics to make peanuts safer. “You would have to get every peanut seed variety in the country changed. Logistically and everything, it would be a challenge.”

Although the Alrgn Bio treatment process uses Alcalase, which has already been used in food products, the F.D.A. would most likely have to scrutinize peanuts that would be marketed as less allergenic. It remains uncertain how regulators might view claims like “hypoallergenic” or “reduced allergen.” Government regulations in the United States tightly control how claims about allergens can be made to consumers: If an alcoholic beverage, for instance, has gluten-based starting ingredients, it cannot be labeled “gluten free,” even if in the end it contains no detectable gluten. The makers of Omission beers, who remove gluten from barley during the brewing process using Brewers Clarex, another industrial enzyme, label their products in the United States as “crafted to remove gluten.” Still, these beers have a strong following, as does Lactaid milk, which relies on the enzyme lactase to break down the lactose sugar that causes digestive problems in some people when they consume dairy.

Genetic manipulation hasn’t worked to remove all of the allergens found in peanuts, and it faces an added hurdle, since many consumers are uncomfortable with the idea of genetically modified foods. The scientists bioengineering peanuts to lack allergens are hoping to eliminate genes from the final product, rather than introduce any new ones. This can be an important distinction in the eyes of some regulators. In April the U.S.D.A. determined that a white button mushroom genetically edited using Crispr technology to resist browning wasn’t subject to special oversight as a potential weed or pest by the agency, because the final product was free of foreign DNA. As yet, though, the F.D.A. has not approved label claims of reduced allergenicity in any foods sold in the United States.

There’s evidence that food producers may be open to adopting innovative peanuts. In the 1990s scientists announced they had developed peanut varieties that contained higher levels of oleic acid, which is thought to be healthy for the heart and which also gives the nuts a longer shelf life. These peanuts have gained strong industry acceptance: Last year, Mars Chocolate, the maker of peanut M&Ms and Snickers, announced that its North American products would contain only this kind by 2017. But James R. Baker Jr., an allergist who leads the nonprofit advocacy group Food Allergy Research & Education, is also unsure whether you can make a peanut that’s guaranteed to be safer and whether consumers will go for it. “There’s a theoretical potential there,” he says. “They’ll test in the marketplace whether this is rational. That will be the acid test.”

Burks, whose research into peanut allergies opened up the field, has focused his own work on therapies that retrain the immune system of afflicted individuals by exposing them to tiny amounts of this food. He is cautiously optimistic about altered peanuts, granting that they could perhaps one day be used for this sort of retraining. But Burks says that the goal of preventing accidental deaths by replacing peanuts for the general population with a safer version becomes ever more elusive as scientists discover more about how much the nature and strength of peanut allergy can vary from one individual to the next. “Everything we’ve learned about allergic proteins since the 1990s tells us the more we know, the harder it becomes to avert them.”

Roxanne Khamsi is a journalist who has written for Scientific American, Slate and Newsweek and is chief news editor for Nature Medicine. She teaches at Stony Brook University’s Alan Alda Center for Communicating Science.

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